TMP195

TMP195 is a potent and selective class IIa HDAC inhibitor with IC50s of 59 nM, 60 nM, 26 nM and 15 nM for HDAC4, HDAC5, HDAC7 and HDAC9, respectively^[1].

TMP195 promotes the differentiation of human monocytes into antigen presenting cells with IL-4 and GM-CSF in vitro^[2]. In renal tubular cell,TMP195 inhibited LPS-induced upregulation of multiple proinflammatory cytokines/chemokines, including intercellular adhesion molecule-1, monocyte chemoattractant protein-1, tumor necrosis factor-α, and interleukin-1β, and accumulation of inflammatory cells in the injured kidney^[3]. As a potent and selective inhibitor of class IIa histone deacetylase, In vitro TMP195 treatment significantly enhances drug-induced apoptosis and sensitizes multidrug-resistant cancer cells overexpressing ABCB1 or ABCG2 to anticancer drugs^[5].TMP195 enhances phagocytic responses to antibody-opsonised CLL cells and E. coli within 30 min of treatment. The enhanced response is phenocopied by knockdown of the Class IIa HDAC, HDAC7, or by low concentrations of the pan-HDAC inhibitor, vorinostat^[6].

TMP195 reduces tumor burden and lung metastasis in vivo by regulating macrophage phenotype, changing tumor microenvironment. TMP195 induces recruitment and differentiation of highly phagocytic and stimulating macrophages within tumors. TMP195 significantly reduces proliferating tumor cells, especially in the leading edge of tumor^[2].In mice,Pharmacological inhibition of HDAC9 with the class IIa HDAC inhibitor TMP195 attenuates lesion formation by reducing endothelial activation and leukocyte recruitment along with limiting proinflammatory responses in macrophages^[4].In C57BL/6J mice, Treatment of L6 myotubes with HDAC inhibitors TMP195 or skeletal muscle with a combination of HDAC and sirtuin inhibitors increased tubulin and pan-protein acetylation, demonstrating effective impairment of HDAC and sirtuin deacetylase activities^[7].

References:
[1]: Lobera M, Madauss KP, et,al.Selective class IIa histone deacetylase inhibition via a nonchelating zinc-binding group. Nat Chem Biol. 2013 May;9(5):319-25. doi: 10.1038/nchembio.1223. Epub 2013 Mar 24. PMID: 23524983.
[2]: Guerriero JL, Sotayo A, et,al. Class IIa HDAC inhibition reduces breast tumours and metastases through anti-tumour macrophages. Nature. 2017 Mar 16;543(7645):428-432. doi: 10.1038/nature21409. Epub 2017 Mar 8. PMID: 28273064; PMCID: PMC8170529.
[3]: Zhang W, Guan Y, et,al. Class IIa HDAC inhibitor TMP195 alleviates lipopolysaccharide-induced acute kidney injury. Am J Physiol Renal Physiol. 2020 Dec 1;319(6):F1015-F1026. doi: 10.1152/ajprenal.00405.2020. Epub 2020 Oct 5. PMID: 33017186; PMCID: PMC7792695.
[4]: Asare Y, Campbell-James TA, et,al. Histone Deacetylase 9 Activates IKK to Regulate Atherosclerotic Plaque Vulnerability. Circ Res. 2020 Aug 28;127(6):811-823. doi: 10.1161/CIRCRESAHA.120.316743. Epub 2020 Jun 17. PMID: 32546048.
[5]: Wu CP, Lusvarghi S, et,al.The Selective Class IIa Histone Deacetylase Inhibitor TMP195 Resensitizes ABCB1- and ABCG2-Overexpressing Multidrug-Resistant Cancer Cells to Cytotoxic Anticancer Drugs. Int J Mol Sci. 2019 Dec 29;21(1):238. doi: 10.3390/ijms21010238. PMID: 31905792; PMCID: PMC6981391.
[6]: Burgess M, Chen YCE, et,al. HDAC7 is an actionable driver of therapeutic antibody resistance by macrophages from CLL patients. Oncogene. 2020 Aug;39(35):5756-5767. doi: 10.1038/s41388-020-01394-w. Epub 2020 Jul 24. Erratum in: Oncogene. 2021 Feb;40(6):1203. PMID: 32709923.
[7]: Martins VF, Begur M, et,al.Acute inhibition of protein deacetylases does not impact skeletal muscle insulin action. Am J Physiol Cell Physiol. 2019 Nov 1;317(5):C964-C968. doi: 10.1152/ajpcell.00159.2019. Epub 2019 Aug 28. PMID: 31461343; PMCID: PMC6879879.